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Abstract

Background: One in every 9 persons age 65 years and older and 1 in every 3 persons age 85 years and older has Alzheimer’s disease. The etiology of the disease is not well understood. For decades, cerebral accumulation of amyloid proteins and tau neurofibrillary tangles has been thought to be the culprit. While amyloid and tau are still risk factors, mounting evidence is shifting the framing of Alzheimer’s to a disease of disordered metabolism. Individuals with Alzheimer’s consistently exhibit decreased cerebral metabolism due to impaired glucose utilization. Those with chronic hyperglycemia present with greater accumulation of cerebral amyloid plaques and more severe reductions in brain metabolism increasing Alzheimer’s risk. Little data exist exploring the role of dietary intake, namely carbohydrate intake and glycemic load, in amyloid processing or altering brain bioenergetics through manipulation of dietary macronutrient intake. Methods: Two studies were conducted to assess the questions proposed in this dissertation. First, we performed cross-sectional analyses of dietary glycemic measures (high glycemic load diet pattern [HGLDiet], sugar intake, carbohydrate intake and glycemic load) with cerebral amyloid burden (measured by florbetapir F-18 PET) and cognitive performance in 128 cognitively normal older adults participating in the University of Kansas Alzheimer’s Prevention Program. Second, we recruited 15 participants with a diagnosis of Alzheimer’s disease to a single-arm clinical trial of a medium chain triglyceride supplemented ketogenic diet (MCT-KD) for 3 months to assess feasibility and obtain preliminary efficacy data. At month 3, participants terminated the MCT-KD and resumed a normal diet for a 1-month washout period. Ketone generation was monitored through daily checking of urinary ketone status by the participant and monthly serum β-hydroxybutyrate assessment. Dietary intake was collected through monthly 3-day food records. Cognition was measured through administration of the Mini-Mental State Exam and the Alzheimer’s Disease Assessment Scale-cognitive subscale at baseline, after 3 months of the dietary intervention and following a 1-month discontinuation of the MCT-KD. Results: In the observational study, individuals with elevated amyloid had greater consumption of the HGLDiet pattern (p=0.015). The HGLDiet pattern was positively associated with amyloid burden both globally and in all regions of interest independent of age, gender, and BMI (all p-values ≤ 0.001). Individual dietary glycemic measures (sugar intake, carbohydrate intake and glycemic load) were also positively associated with global amyloid load and nearly all regions of interest independent of age, gender and BMI (p-values ≤ 0.05). Higher sugar consumption was associated with poorer global cognitive performance (Global Composite and Mini-Mental State Exam) and performance on subtests of Digit Symbol, Trailmaking B, and Block Design when controlled for age, gender, and education. In the clinical trial, the MCT-KD was feasible in individuals with AD as 10 of the 15 participants produced urinary and serum ketones during the 3-month intervention. Urinary acetoacetate was detected an average of 54.5 (60.6%) days of the intervention in study completers. Serum β-hydroxybutyrate was significantly elevated above baseline at all 3 monthly time points during the diet intervention (p≤0.001 for each). Improvements in ADAS-cog scores were observed from baseline to month 3 (4.1 point mean improvement, p=0.02) and improvements diminished after the 1-month washout. Conclusion: A dietary pattern high in carbohydrate, especially highly glycemic carbohydrates, was associated with biomarkers for AD risk. A ketogenic diet restricted in carbohydrate and higher in fat may elicit cognitive benefit in individuals already diagnosed with AD.